PROJECT SUMMARY ABSTRACT Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality and complicates 5-8% of all pregnancies. This pregnancy complication is defined by de novo onset of hypertension and proteinuria after 20 weeks of gestation and has been linked to a high incidence of chronic diseases later in life, including cardiovascular disease, diabetes mellitus, and renal disease. Thus, directed therapy is critically important to improve both maternal and neonatal outcomes. However, to date, no effective therapy for this syndrome is clinically available. The most effective treatment is delivery of the placenta. Our recent novel findings suggest that PE and Alzheimer's disease (AD) share a common etiology of proteinopathy and impaired autophagy and that accumulation of protein aggregates in the PE placenta directly results from dysregulated lysosomal biogenesis. This work has led to search for therapeutic interventions that uniquely target impaired autophagy and toxic protein aggregation. Our pilot experiments suggest that a non-mammalian disaccharide, Trehalose, restored autophagy and inhibited protein aggregation in a humanized mouse model of PE as well as in hypoxia (1% O2)-exposed primary human trophoblasts. In the mouse model, Trehalose could be effective in both prevention and treatment settings. The primary trophoblast experiments strongly suggested that hypoxia inactivated calcineurin, a phosphatase that promotes nuclear translocation of the transcription factor TFEB, a master regulator of lysosomal biogenesis proteins, LAMP1, LAMP2 and cathepsinD. The Project leaders propose to expand on these intriguing preliminary results and propose novel experiments to assess the efficacy of Trehalose for treatment of PE. Moreover, they plan to examine whether Trehalose can reverse transcriptome-wide changes associated with PE in both the in vivo and in vitro models. The Specific Aims proposed in this Supplement grant proposal adhere to the overarching goal of establishing pre-clinical and cellular models to assess their significance in reversing PE-associated pathological pathways. Based on mechanistic insights into the pathogenesis of PE, our proposed research will assess the ability of a small, inexpensive, and non-mammalian disaccharide to prevent and treat PE. We will also investigate its safety profile in vivo. This straight forward intervention and reversal of PE pathology in a well-defined pre-clinical model may provide a basis for clinical evaluation of Trehalose in pregnant women.